Variation in Institutional Review Board Responses to a Standard Protocol for a Multicenter Clinical Trial

Multicenter clinical trials require approval by multiple local institutional review boards (IRBs). The Multicenter Airway Research Collaboration mailed a clinical trial protocol to its U.S. investigators and 44 IRBs ultimately reviewed it. OBJECTIVE: To describe IRB responses to one standard protocol and thereby gain insight into the advantages and disadvantages of local IRB review. METHODS: Two surveys were mailed to participants, with telephone follow-up of nonrespondents. Survey 1 was mailed to 82 investigators across North AMERICA: Survey 2 was mailed to investigators from 44 medical centers in 17 U.S. states. Survey 1 asked about each investigator's local IRB (e.g., frequency of meetings, membership), whereas survey 2 asked about IRB queries and concerns related to the submitted clinical trial. RESULTS: Both surveys had 100% response rate. Investigators submitted applications a median of 58 days (interquartile range [IQR], 40--83) after receipt of the protocol, and IRB approval took an additional 38 days (IQR, 26--62). Although eight applications were approved with little or no changes, IRBs requested an average of 3.5 changes per site. Changes involved study logistics and supervision for 45%, the research process for 43%, and the consent form for 91%. Despite these numerous requests, all eventually approved the basic protocol, including inclusion criteria, intervention, and data collection. CONCLUSIONS: The IRBs showed extreme variability in their initial responses to a standard protocol, but ultimately all gave approval. Almost all IRBs changed the consent form. A national, multicenter IRB process might streamline ethical review and warrants further consideration.     

Variation in Institutional Review Board Responses to a Standard, Observational, Pediatric Research Protocol

Background: Multicenter studies are becoming more common, and variability in local institutional review board (IRB) assessments can be problematic.
Objective: To investigate the variability of IRB responses to a multicenter observational study of children presenting to emergency departments.
Methods: The authors collected the original IRB applications, subsequent correspondence, and a survey assessing submission timing and response and the nature of IRB queries. The study was conducted as part of the Emergency Medicine Network http://www.emnet-usa.org
Results: Of 37 sites initiating the IRB process, 34 (92%) participated in this IRB-approved study. Institutional review boards returned initial applications in a median of 19 days (IQR, 11–34 d), and 91% considered the protocol to be minimal risk. Of 34 submissions, 13 required no changes, 18 received conditional approvals, and 3 were deferred. The median time from initial submission to final approval was 42 days (IQR, 27–61 d). Seven sites did not participate in patient recruitment: two had institutional issues, one obtained IRB approval too late for participation, and four sites (12%) reported that IRB hurdles contributed to their lack of participation. Nonetheless, 68% of sites that recruited patients reported that the overall experience made them more likely to participate in future multicenter research.
Conclusions: There was substantial variation in IRB assessment of a standard protocol in this study. The burden of the application process contributed to some investigators not participating, but the majority of investigators remain enthusiastic about multicenter research. A national IRB may streamline the review process and facilitate multicenter clinical research.     

Conducting research using the emergency exception from informed consent: the Public Access Defibrillation (PAD) Trial experience

BACKGROUND: The Public Access Defibrillation (PAD) Trial, a prospective, multicenter, randomized clinical trial comparing two prehospital resuscitation strategies, was conducted under the regulations for exception from informed consent (21CFR50.24) in 24 communities in North America. These regulations place additional requirements for human subject protection on investigators and Institutional Review Boards (IRBs), including conducting community consultation (CC) and public disclosure (PD). OBJECTIVE: To describe the IRB approval process at study sites and the number and types of community consultation and public disclosure activities conducted. METHODS: The 24 study sites in the United States and Canada submitted IRB applications, CC and PD plans, and a structured report on IRB process and investigator perceptions to the Clinical Trial Center at the University of Washington. RESULTS: The primary IRBs for all 24 trial sites and a total of 101 IRBs approved the study. The median interval from submission to approval was 108 days (IQR 43-196), and the mean number of revisions was two (range 0-7). Investigators conducted nearly 12,000 activities to achieve CC and PD; activities varied greatly from site to site in both type and quantity. CONCLUSION: The length of time to obtain IRB approval and the extent of community consultation and public disclosure varied greatly among trial sites in meeting the current regulations for conducting emergency research with exception from informed consent. This suggests that more specific guidance may be useful and that determination of effective strategies for community consultation and public disclosure is needed.     

New drug approval times and clinical evidence in Japan

BACKGROUND: Although overall Japanese approval times declined after the establishment of a new review agency, they still vary significantly from one new drug application (NDA) to another. The causes of these variations have not been investigated quantitatively. OBJECTIVE: To investigate associations between the approval times and properties of the NDAs such as the results and quality of clinical trials and to examine the Japanese NDA review system. METHODS: For the NDAs approved between 1996 and 2003, the characteristics of NDAs including application and approval dates, review status, applicant characteristics, and clinical results were obtained from a survey and other public sources. Regulatory characteristics at different times including the number of NDAs in backlog were also estimated from several sources. RESULTS: Approval times varied significantly across therapeutic categories, review teams, and before and after the new review agency. Use of consultation services and prior number of NDA submissions were negatively associated with the length of approval times. Merger and acquisition experience of the applicants, the amount of clinical data, and the number of NDAs in backlog in the review teams were associated with longer approval times. The way of efficacy establishment was not associated with the length of approval times, but safety profiles of products were associated with the time. Use of foreign clinical data was generally not associated with the length of approval times. CONCLUSIONS: Several characteristics of applicants, burdens on the reviewers, clinical data package, and regulatory mandates such as predefined time-line goals were associated with the outcome of the review process in Japan.     

Characteriation of clinical data packages using foreign data in new drug applications in Japan

The objective of this research was to characterize clinical data packages (CDPs) of new drug applications (NDAs) using foreign data based on the International Conference on Harmonization (ICH) E5 guideline. Official review reports of NDAs approved in Japan between January 1999 and April 2005 were examined. Those NDAs considered by the official reviewers to be approved based on the ICH E5 guideline (E5-NDAs) were identified and classified into six categories of approval requirements in Japan. The details of pivotal clinical efficacy studies in the CDPs were examined. Forty-one NDAs were identified as E5-NDAs. Pivotal clinical studies conducted in Japan were required by the E5-NDAs, except for nine of those in which the foreign clinical studies reduced Japanese clinical studies in the CDPs. Given the differences in approval requirements among regions, the acceptability of foreign clinical data to Japanese approval is limited.     

Japanese Regulatory System for Approval of Off-Label Drug Use: Evaluation of Safety and Effectiveness in Literature-Based Applications

BackgroundAlthough approved elsewhere, many drug indications remain unapproved in Japan. Many of these unapproved indications are off-label, which, despite strong supporting evidence, are not covered by the Japanese health insurance system. To address this situation, the Ministry of Health, Labour and Welfare of Japan announced in 1999 that, under certain conditions, it would approve a new supplement for a drug indication without clinical trials. This approval scheme involved application evaluation using literature-based evidence; however, the type of indications and the kind of evidence used in practical applications remain to be clarified.ObjectiveThis commentary sought to investigate the factors that contribute to the approval of individual applications through an analysis of review reports and to assess the outcome of efforts to facilitate the approval of off-label drugs by this approval system that has been used for over a decade in Japan.MethodsData from 80 approvals granted under this scheme were obtained from the official review reports of the Japanese regulatory agency. The following criteria were selected for the analysis of individual applications: review time, therapeutic class, application category under Japanese regulations, international approval status, postapproval monitoring plan, and variety and quantity of literature evidence. The literature used as a source of evidence was categorized into 4 types: (I) standard textbooks, (II) standard guidelines, (III) reviews, and (IV) application dossier submitted to the foreign regulatory authorities.ResultsThe number of approvals and applications per year showed no consistent trend. The median (SD) review time was 16.4 (9.0) months, which was not affected by the international approval status or the literature evidence. This approval scheme was applied to not only a new indication (56 applications [70%]) or dosage (9 [11%]) but also a new route of administration (13 [16%]). Of the 80 applications, 46 (58%) had been approved in the United States, the United Kingdom, or both; 11 (14%), in other countries; and 23 (29%), in no country. For 2 approvals, the review reports were not released; the other 78 were based on either standard textbooks or guidelines, while 67 (84%) were based on both. The variety and quantity of literature evidence provided in the application showed no consistent trend with respect to international approval status.ConclusionsPrior approval by foreign authorities, although important, did not appear to be essential for approval in Japan. However, substantiating safety and effectiveness of agents by means of standard textbooks or guidelines was used consistently to obtain approval for off-label use.     

The effect of flumazenil on patient recovery and discharge following ambulatory surgery.

Midazolam is a short-acting agent used for preoperative and conscious sedation. Despite a relatively short half-life, midazolam sedation contributes to postoperative sedation, delays in discharge, and increased costs. Administration of flumazenil, a benzodiazepine antagonist, can reverse the centrally mediated effects of midazolam and facilitate patient recovery and discharge, thereby reducing costs. The purpose of this multicenter study was to determine whether flumazenil antagonism of midazolam decreased the length of postoperative stay following intravenous sedation during local and selected regional procedures. A prospective, double-blinded, and randomized convenience sample of 110 adult patients who underwent procedures lasting 90 minutes or less was used. After receiving institutional review board approval and informed consent, patients received up to 150 micrograms of fentanyl and unlimited midazolam titrated intravenously to effect. Flumazenil or a placebo was administered at the conclusion of the surgical procedure. Cognitive scores were assessed by using the Digital Symbol Substitution Test and picture recall, while sedation scores were assessed by using the Observer's Assessment of Alertness/Sedation Scale. The time between the end of the surgical procedure until the patient met discharge criteria in phases I and II was recorded. Statistical analyses revealed no significant difference in age, height, weight, sex, ASA physical status, amount of midazolam and fentanyl received, time for each group to achieve phase I and phase II discharge criteria, or postoperative congnitive scores. The flumazenil group exhibited less amnesia and sedation than the placebo group on initial arrival in the postanesthesia care unit. Discharge times between the groups were not significantly different. Factors such as staffing and institutional discharge policies were identified as determinants of discharge times.     

Variations in experience in obtaining local ethical approval for participation in a multi-centre study

BACKGROUND: The Department of Health recently issued guidance on how Local Research Ethics Committees (LRECs) should handle an Multi-centre Research Ethics Committee (MREC)-approved application. This process is intended as a rapid standardized approval process, facilitating the execution of clinical trials. AIM: To evaluate if this guidance had led to an efficient process for obtaining local ethical approval. METHODS: Questionnaires were sent by post to Local Investigators of the 56 centres who had obtained LREC approval for the Multi-centre Intrapleural Streptokinase Trial. RESULTS: Replies were received from 51 centres (91%). A total of 25 296 pieces of paper and 62 h of photocopying time were required to meet the 51 LRECs' requirements. LREC meetings ranged from weekly to bimonthly, with only 24 (47%) having a 'fast track' system in place. Applications took a median of 27 (1-90) days from submission to first being considered, with local investigators spending 3.27 (0.5-15) h on each submission. Nineteen (37%) of the local investigators felt the LREC/MREC interface did not work well and 17 (33%) were at least partly deterred from participating in future trials. DISCUSSION: The guidelines do not seem to have been implemented by all LREC committees, leading to wide variation in local experience.     

Surgical quality assurance in the Ischemic Optic Neuropathy Decompression Trial (IONDT)

The purpose of this article is to report the methods and results of the surgical quality assurance program associated with the Ischemic Optic Neuropathy Decompression Trial (IONDT). A surgical quality assurance committee developed and implemented a quality assurance program for a randomized clinical trial requiring surgical intervention. A surgical technique questionnaire was administered at two times during the study course, and maintenance of surgeon certification required submission and approval of a masked videotape of an optic nerve sheath decompression surgery by each study surgeon. Surgical quality was assessed through completion of surgical report forms and standardized, masked review of operative notes. Rates of compliance and intra- and interreviewer agreement were assessed for each aspect of the program. Twenty-five of 32 surgeons (81%) successfully completed and maintained certification. Item agreement varied from 21-92% among reviewers of satisfactory videotapes and 22-89% on unsatisfactory videotapes. Intrarater agreement for videotape acceptability was 11 of 13 (85%), and for specific surgical steps, 147 of 182 (81%). Operative notes were submitted for 123 of 125 (98%) patients receiving surgery. Interrater agreement on individual items ranged from 73-100%. Classification of individual items was identical on first and second review for 1285 of 1344 (95.6%) items. Overall agreement for individual reviewers was 93.8-97.8%. We conclude that use of a small peer review committee, which developed and oversaw a quality assurance program, allowed for consistent certification and monitoring of surgical performance. This in turn increased the credibility of the IONDT results, which demonstrated no difference in outcome between operated and unoperated groups of patients.     

Timeliness of review and approval of new drugs in Canada from 1999 through 2001: is progress being made?

BACKGROUND: The median time to approval of new drugs in Canada decreased considerably in the mid-1990s, although it continued to be longer than in such countries as Australia, Sweden, the United Kingdom, and the United States. Ongoing concern about approval times pointed to a need for a further international comparison. OBJECTIVE: This study was designed to assess whether there have been continuing improvements in drug approval times in Canada relative to these other countries. METHODS: Application and approval dates of new chemical or biological substances approved for marketing from 1999 through 2001 were requested from the Canadian, Australian, and Swedish regulatory agencies. Information for the United States was derived from publications of the Pharmaceutical Research and Manufacturers of America. The regulatory agency for the United Kingdom does not release application dates, although these were the same as the Swedish application dates for most drugs approved in both countries through the centralized European Union (EU) review procedure. Application dates for drugs licensed under the EU mutual-recognition arrangement or in the United Kingdom only were requested from the relevant pharmaceutical companies. RESULTS: One hundred eighty-six new drugs were approved in >/=1 of the countries studied between January 1999 and December 2001: 17 (9.1%) in all 5 countries, 25 (13.4%) in 4, 27 (14.5%) in 3, 39 (21.0%) in 2, and 78 (41.9%) in 1. Approval times were longer in Canada than in Australia, although not significantly so (median time, 645 and 551 days, respectively). Canadian and Australian approval times were significantly longer than those in Sweden (431 days), the United Kingdom (479 days), and the United States (371 days) (P < 0.001). The annual median approval time in Canada increased in each of the 3 years. The approval times of priority-reviewed drugs in Canada were significantly longer than in the United States (median 317 vs 232 days) but significantly shorter than in Australia (509 days) (both comparisons, P < 0.001). CONCLUSIONS: Overall approval times of new drugs in Canada were longer than those in Australia, Sweden, the United Kingdom, and the United States in the period studied. The findings warrant ongoing monitoring of Canadian drug approval times.     

Azacitidine for the treatment of patients with acute myeloid leukemia with 20%–30% blasts and multilineage dysplasia

Azacitidine is approved in the EU for the treatment of adult patients who are not candidates for allogeneic stem cell transplantation, and who have intermediate-2 risk or high-risk myelodysplastic syndromes, according to the International Prognostic Scoring System. The approval includes the treatment of patients with acute myeloid leukemia (AML) with 20%–30% blasts and multilineage dysplasia, according to the World Health Organization (WHO) classification. This review focuses on the outcomes with azacitidine in this latter group of patients, previously classified as refractory anemia with excess of blasts in transformation, as defined by the French-American-British classification criteria. The main clinical evidence is based on the results of two large phase III clinical trials (Cancer and Leukemia Group B 9221, and AZA-001). The AZA-001 trial shows azacitidine significantly prolongs median overall survival in older patients with low marrow blasts (20%–30%) according to WHO-defined AML, and significantly improved several patient morbidity measures, compared with conventional care regimens. In addition, the review examines the results of azacitidine in combination with other treatments currently used in AML.     

Variability in Institutional Review Board Assessment of Minimal-risk Research

OBJECTIVES: To examine variability in responses from institutional review boards (IRBs) to submission of a proposed minimal-risk survey. METHODS: Identical research proposals to obtain information concerning beliefs about the needs of victims of intimate partner violence via surveys were submitted for IRB approval to three institutions in the Baltimore metropolitan area. One institution is an academic center, one is an inner-city hospital affiliated with the academic center, and the third is a suburban community hospital. The study population consisted of emergency department health care providers and individuals in emergency department waiting areas. RESULTS: Inconsistencies emerged among the three IRBs in the review process itself, the need for participant consent, and the need for revision of the consent form and study protocol. One institution approved the proposal in 15 business days after expedited review. The second institution approved the proposal in 12 business days and waived the requirement for informed consent. The third institution approved the research in 77 business days after three revisions. Questions raised included: methodology for selecting participants; appropriateness of surveying individuals in emergency department waiting areas; a request for background literature to assure that the research questions had not already been answered; and concerns about study methodology and sample size justification. CONCLUSIONS: In this sample, there is considerable variability in IRB processes even for minimal-risk studies.     

Canadian and US drug approval times and safety considerations

BACKGROUND: Approval times of new drugs are frequently longer in Canada than in the US, but it has been argued that reducing approval times might lead to unsafe drugs receiving marketing approval. OBJECTIVE: To compare new drug approval times in Canada and the US over a 10-year period and to relate them to safety discontinuations. METHODS: Application and approval dates of all new drugs except diagnostic products, new salts, esters, isomers, and dosage forms of already-marketed drugs, as well as combinations containing previously approved substances approved in the US and Canada between January 1992 and December 2001 were obtained from the respective drug regulatory agencies and other sources. Information about drugs discontinued for safety reasons was obtained from the agencies' publications and Web sites and from journal articles. RESULTS: New drug approval times were significantly longer in Canada than in the US. The difference occurs in all drug categories and by review type (priority/standard). However, the proportion of new drugs approved and later discontinued for safety reasons from the Canadian market (2.0%) was just over half that in the US (3.6%). CONCLUSIONS: When serious drug safety problems were identified in a timely manner after US approval, the products were not subsequently approved in Canada. Canada avoided potential dangers because its longer approval times provided an opportunity to observe actual market experience in other countries. However, the trade-off is that new drugs, including those for conditions for which current therapy has limited efficacy, take significantly longer to be approved in Canada and, hence, to be available to Canadians.     

Readability of Participant Informed Consent Forms and Informational Documents: From Phase 3 COVID-19 Vaccine Clinical Trials in the United States

ObjectiveTo assess the readability of the informed consent forms from the phase 3 COVID-19 vaccine trials conducted in the United States.Patients and MethodsEnglish consent forms were used for patients in phase 3 COVID-19 vaccine clinical trials. Consent forms were obtained in October 2020. Using Microsoft Word tools, we analyzed the readability (ie, the ease of reading) of written consent forms and informational documents from phase 3 COVID-19 vaccine clinical trials in the United States from the following manufacturers: AstraZeneca, Moderna, Pfizer, Johnson & Johnson, and Novavax.ResultsOwing to low readability and several format factors, this study determined that none of the consent forms or informational documents from the recent phase 3 COVID-19 vaccine clinical trials conducted in the United States met readability standards at the recommended 7th grade readability level for the average vaccine research volunteer in any readability category. The average English-speaking vaccine trial volunteer would have great difficulty comprehending the information provided in the consent forms and informational documents. To ensure that study subjects receive and fully comprehend information regarding a clinical study and can provide reliable consent, greater attention should be given to the development and use of simplified consent forms, multimedia formatting, personal discussion, and comprehension assessments.     

The effect of long-term storage on measured plasma lactate concentrations and prospective lactate results from a multicenter trial of antiretroviral therapy.

Plasma lactate measurements are typically performed in real time, limiting their usefulness in multicenter or longitudinal studies. To determine the stability of lactate specimens, blood was drawn in sodium fluoride/potassium oxalate tubes from 13 volunteers before and after 5 min of handgrip exercise to intentionally increase lactate concentrations. Plasma was stored at -70 degrees C. Aliquots were assayed in real time and after 1, 3, 6, 9, 12, 18, and 24 months. Real-time lactate concentrations measured at baseline ranged from 0.52 to 2.23 mmol/L before and from 2.91 to 11.04 mmol/L after handgrip exercise. Using a linear mixed model, the estimated change from baseline at month 24 was 1.67% (95% confidence interval, -0.70% to 4.03%) for pre-exercise samples and 0.39% (95% CI, -1.13% to 1.91%) for post-exercise samples. Stored serial specimens from 232 HIV-infected subjects in a multicenter trial of antiretroviral therapy were also assayed centrally. Among those, median plasma lactate increased from baseline to 64 weeks by 0.4 mmol/L with zidovudine+lamivudine treatment and by 0.6 mmol/L with didanosine+stavudine (each p<0.001 from baseline; p=0.04 for difference between groups over time). When performed as in this study, frozen storage with central batch lactate analysis is appropriate for prospectively collected samples in multicenter trials.     

Delays in psychiatric drug development in Japan

What is known and Objective: The lag in the approval and development of psychiatric drugs between Japan and other countries has been a major issue both for patients with psychiatric diseases and for psychiatrists. The objective of this study was to analyse factors contributing to delays in launching new psychiatric drugs in Japan. Methods: We analysed data from Japan, the USA, and the UK for the approval of 23 standard psychiatric drugs and examined potential factors that might have contributed the delay of their launch. Results: Of the 23 standard psychiatric drugs, all of which were approved in the USA and the UK, only 13 were introduced in Japan between September 2000 and July 2011. None of their development strategies adopted the ICH E5 guideline on simultaneous development of drugs on a global scale. Twelve of the 13 drugs (not including atomoxetine) were approved in Japan after their approval in the USA and the UK. The median review time (from approval application to approval) of these 13 drugs in Japan was 23 months, which was considerably longer than those of the US Food and Drug Administration and European Medicines Agency (10·0 and 13·5 months, respectively). The 10–13‐month difference in review time cannot explain the overall 87‐ and 51‐month delay in Japan after approval in the USA or UK. What is new and Conclusion: There remains a large gap between Japan and Western countries, such as the USA and the UK, with regard to access to standard psychiatric drugs, despite several important reforms in the Japanese drug approval system.     

The informed consent process and the use of the exception to informed consent in the clinical trial of diaspirin cross-linked hemoglobin (DCLHb) in severe traumatic hemorrhagic shock. DCLHb Traumatic Hemorrhagic Shock study group.

In the clinical trial of diaspirin cross-linked hemoglobin (DCLHb), optimal therapy required the immediate enrollment of patients with severe, uncompensated, traumatic hemorrhagic shock. When it was not feasible to obtain prospective consent, an exception to informed consent was used according to FDA regulation 21 CFR 50.24. OBJECTIVES: To examine the informed consent process and the use of the consent exception and consent to continue (CTC), and to describe the patients for whom this process was used. METHODS: This was a multicenter, randomized, controlled, single-blinded efficacy trial of DCLHb as an adjunct to standard therapy in the treatment of severe, traumatic hemorrhagic shock. Patients with unstable vital signs or a critical base deficit were treated, with a primary study endpoint of 28-day mortality. RESULTS: During the 11-month study period, 112 patients were randomized in 18 U.S. trauma centers, and data from 98 of the infused patients were analyzed. Prospective consent was obtained from two patients, three family members, and one legally authorized representative (LAR) (6%). Consent to continue was requested for 89 patients (89%), and full participation was granted for 87 of these patients (98%). Consent to continue was provided by 54 (98%) of the 55 patients approached. The mean number of days for family/LAR CTC was 1.1 +/-3.8 days, and 50% of the time it was obtained on the day of study enrollment. Patient CTC was obtained in an average of 13 +/- 23 days, with a median of four days. Patients treated in this protocol were more likely to have sustained penetrating trauma than the overall trauma patient population treated in these trauma centers (44% vs 21%, p = 0.002). CONCLUSIONS: Informed consent in this study of an emergent therapy most often involved the use of the consent exception and consent to continue, the latter of which occurred in a timely manner. Nearly all of those who were approached for CTC approved full participation in the study, suggesting acceptance of the process outlined in the new regulations. Patients treated in a hemorrhagic shock clinical trial may differ from the general trauma patient population.